Khalid Al-Rasadi, BSc, MD, FRCPC

Head of Biochemistry Department, SQU

Head of Lipid and LDL-Apheresis Unit, SQUH

President of Oman society of Lipid & Atherosclerosis

(OSLA)

Lipid Metabolism in Familial

Hypercholesterolemia

Disclosures

• Honoraria for Speakers Bureau (Pharma)

AstraZeneca, Sanofi, Pfizer

• Advisory Boards: Sanofi, Aegerion, AstraZeneca

• Research Funding: Pfizer

Cholesterol Importance

➢ A stabilizing component of cell membranes

➢ A precursor of bile salts

➢ A precursor of steroid hormones

➢ A cholesterol precursor is converted to cholecalciferol (vit. D)

⚫ Synthesis

⚫ Primary synthetic sites are extrahepatic, but liver is key regulator of homeostasis

⚫ Absorption

⚫ Largest source is biliary secretion, not diet.

⚫ Normal absorption: 50%

⚫ For cholesterol to be absorbed it must:

⚫ undergo hydrolysis (de-esterification by esterases)

⚫ be incorporated into micelles

⚫ be taken up by cholesterol transporter

⚫ be re-esterified and incorporated into chylomicrons

NORMAL CHOLESTEROL METABOLISM

400 mg/day

1,300 mg/day

17,400 mg/day

850 mg/day

NORMAL CHOLESTEROL ABSORPTION

Oil phase

HMG CoA Reductase(More Than Cholesterol Synthesis)

Acetyl CoA

HMG CoA

Mevalonate

Farnesyl Pyrophosphate

Cholesterol

HMG CoA Reductase

Isopentenyl

adenine

(transfer RNA)

Prenylation of

signalling peptides

(ras, rho, etc.)Ubiquinones

(CoQ-10, etc.)Dolichols

Inhibition of other key products of mevalonate may relate to

nonlipid effects & rare side effects of statins.

Lipoprotein Metabolism and Atherosclerosis

LDL

clearance

Lambert et al. J. Lipid Res. 2012. 53: 2515–2524.

Receptor-Mediated Endocytosis of Lipoproteins

• LDL receptor are located at coated pits, which also contain clathrin

• Vesicles fuse with lysosome where cholesterol esters are hydrolyzed into cholesterol & re-esterified by ACAT

• This avoids damaging effects of high concentrations of free cholesterol on membrane

LDL-Receptors

Endosome Lysosome

Amino

acids

Cholesterol

LDL

Cholesteryl ester

(storage)LDL

Receptors

HMG-CoA

reductase

LDL

LDL Receptor (apoB-E receptor)

ACAT

Regulates cholesterol synthesis and plasma cholesterol levels

SREBP

PCSK9

• Proprotein convertase subtilisin/kexin type

9 (PCSK9)

• the 9th member of the proprotein

convertase family of proteins that activate

other proteins

• involved in the degradation of low-density

lipoprotein (LDL) receptors in the liver.

The LDLR Pathway

Lipoproteins

Function:

➢ Lipid transport (cholesterol, cholesterol esters, triacylglycerols, phospholipids)

Structure:

A nucleus: triacylglycerols, cholesterol esters

A shell: phospholipids, apoproteins, cholesterol

Composition of lipoproteins

Apolipoproteins

Major function:

➢ structure, solubility, activation of enzyme, ligands for receptors

Apoprotein Function

Apo A-I activates LCAT, structural component of HDL

Apo B-48 Assembly and secretion of chylomicrons

Apo B-100 VLDL assembly and secretion; structural protein

of VLDL, IDL and LDL; ligand for LDL receptor

Apo C-II Activator of lipoprotein lipase (LPL)

Apo E ligand to LDL receptor; ligand to Apo E receptor

Familial Hypercholesterolemia: Prevalence and Risk

• FH is caused by genetic mutations passed on by:

• One parent (heterozygous, HeFH)1

• Both parents (homozygous, HoFH)1

• HoFH prevalence ranges from 1 in 160,000 to 1 in 250,0002,3

• Individuals with HoFH have extremely high LDL-C levels (>500 mg/dL) and premature CV risk4

• Many with HoFH experience their first coronary event in childhood or adolescence4

• HeFH prevalence ranges from 1 in 200 to 1 in 2503

• Individuals with HeFH can present with LDL-C levels 90 to 500 mg/dL and have premature CV risk4

• On average, individuals with HeFH experience their first coronary event at age 42 (about 20 years younger than the general population)4

• Early treatment is recommended for all individuals with FH, with a goal of reducing LDL-C levels by 50% from baseline3

Abbreviations: CV, cerebrovascular; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-

density lipoprotein cholesterol.

1. Zimmerman MP. Am Health Drug Benefits. 2015;8:436-442; 2. Goldstein J, et al. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995: 1981-

2030; 3. Bouhairie VE, et al. Cardiol Clin. 2015;33:169-179; 4. Turgeon RD, et al. Can Fam Physician. 2016;62:32-37.

laboratory tests in FH

• Secondary hypercholesterolemia causes

• Genetic diagnosis

• LDL Receptor activity

• PCSK9 levels

• Lp(a) levels

Other genetic disorders

• Lysosomal Acid Lipase deficiency

•Sitosterolemia (Phytosterolemia)

• lecithin cholesterol acyltransferase deficiency

LDL-C Overlap

Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia

Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490

Plasma levels of PCSK9 and phenotypic variability in

familial hypercholesterolemia

Lipoprotein (a)

• An LDL + apolipoprotein a

• Different lengths of apo a (kringles) caused

by a variable number of kringle IV repeats

• More kringles = lower Lp(a) levels

• Hepatic synthesis

• Lp(a) plasma concentrations are highly heritable

and mainly controlled by the apolipoprotein(a)

gene [LPA] located on chromosome 6q26-27.

apolipo-

protein(a)

LDL-like

particle

KIV-2 copy

number

variant:

2 to >40

repeats

Koschinsky et al. Cur Opin Lipidol 2004;15:167-174

LIPOPROTEIN (a):

mechanisms of atherogenesis

Homology with plasminogen (= impaired fibrinolysis)

Binds to macrophages → foam cell formation

Binds to platelets (inhibition or stimulation?)

Deposition of cholesterol into plaques?

Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23

Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23

Typical distributions of lipoprotein(a) levels in the general population.

Nordestgaard B G et al. Eur Heart J 2010;31:2844-2853

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org

LIPOPROTEIN (a) MEASUREMENT

• Quantitative Lp(a) measurements

– rocket immunoelectrophoresis

– rate and endpoint nephelometry

– turbidimetry

– radio-immuno assays

– enzyme immuno assays (ELISA)

– dissociation-enhanced lanthanide fluorescent

immunoassay (DELFIA)

Lipoprotein(a) KIV-2 quartile

(mg/dL)

Multifactorially adjusted hazard ratio

(95% confidence interval)

Trend: p<0.001 Trend: p<0.001

1st

2nd

3rd

4th

50 40 30 20 10 1.0 1.5 2.0

Figure. Levels of lipoprotein(a) and risk of myocardial infarction by KIV-2 genotype.

Trend p<0.001

50 40 30 20 10

1st

2nd

3rd

4th

1.0 1.5 2.0

Lipoprotein(a)

(mg/dL)KIV-2

quartile

Hazard ratio

(95% CI)

Trend p<0.001

Risk of Myocardial Infarction

Trend p<0.001

Kamstrup et al. JAMA 2009; 301: 2331-9

Clarke et al. New Engl J Med 2009; 361: 2518-28